De Vita et al. BMC Cancer (2016) 16:709 DOI 10.1186/s12885-016-2671-9

RESEARCH ARTICLE

Open Access

NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice Ferdinando De Vita1*, Jole Ventriglia1, Antonio Febbraro2, Maria Maddalena Laterza1, Alessio Fabozzi1, Beatrice Savastano1, Angelica Petrillo1, Anna Diana1, Guido Giordano2, Teresa Troiani1, Giovanni Conzo3, Gennaro Galizia3, Fortunato Ciardiello1 and Michele Orditura1

Abstract Background: Pancreatic adenocarcinoma is an aggressive disease with poor prognosis. In a randomized phase III trial, combination of Nab-paclitaxel (Nab-P) plus gemcitabine showed superior activity and efficacy in first-line treatment compared with gemcitabine alone. Methods: Nab-P is not dispensed in Italy; however, we obtained this drug from our Ethics Committee for compassionate use. The aim of this study was to evaluate the efficacy and safety profile of this Nab-P and gemcitabine combination in a cohort of patients treated outside clinical trials. From January 2012 to May 2014, we included 41 patients with advanced pancreatic adenocarcinoma receiving combination of 125 mg/m2 Nab-P and 1 g/m2 gemcitabine on days 1, 8 and 15 of a 28-day cycle, as first-line treatment. Median age of patients was 67 (range 41–77) years, and 11 patients were aged ≥70 years. Results: Eastern Co-operative Oncology Group performance status was 0 or 1 in 32 patients (78 %) and 2 in nine patients (22 %). Primary tumor was located in the pancreatic head or body/tail in 24 (58.5 %) and 17 (41.5 %) patients, respectively, and nine patients had received biliary stent implantation before starting chemotherapy. Median carbohydrate antigen 19–9 level was 469 U/l (range 17.4–61546 U/l) and 29 patients (70.7 %) had referred pain at the time of diagnosis. Patients received a median six cycles (range 1–14) of treatment. Overall response rate was 36.6 %; median progression-free survival was 6.7 months [(95 % confidence interval (CI) 5.966–8.034), and median overall survival was 10 months (95 % CI 7.864–12.136). Treatment was well tolerated. No grade 4 toxicity was reported. Grade 3 toxicity included neutropenia in 10 patients (24.3 %), thrombocytopenia in five (12 %), anemia in three (7.3 %), diarrhea in four (9.7 %), nausea and vomiting in two (4.9 %), and fatigue in six (14.6 %). Finally, pain control was achieved in 24 of 29 patients (82.3 %) with a performance status improvement of 10 % according to the Karnofsky scale. Conclusions: Our results confirm that combination of gemcitabine plus Nab-P is effective both in terms of overall response rate, progression-free survival and overall survival, with a good safety profile. Keywords: Metastatic pancreatic cancer, Combination chemotherapy, Nab-paclitaxel, Gemcitabine (Continued on next page)

* Correspondence: [email protected] 1 Division of Medical Oncology, Department of Internal and Experimental Medicine “F. Magrassi”, Second University of Naples - School of Medicine, c/o II Policlinico, Via Pansini, 5, 80131 Naples, Italy Full list of author information is available at the end of the article © 2016 The Author(s). Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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(Continued from previous page)

Abbreviations: ALT, Alanine amino transferase; AST, Aspartate amino transferase; CBR, Clinical benefit rate; CI, Confidence interval; CR, Complete response; DCR, Disease control rate; G, Gemcitabine; HR, Hazard ratio; KPS, Karnofsky performance status; Nab-P, Nab-Paclitaxel; NLR, Neutrophil to lymphocyte ratio; ORR, Objective response rate; OS, Overall survival; PDAC, Pancreatic ductal adenocarcinoma; PFS, Progression free survival; PR, Partial responses

Background Pancreatic adenocarcinoma represents ~3 % of newly diagnosed cancers annually worldwide [1]. It is an aggressive disease and despite the efforts of the past few decades, the 5-year overall survival (OS) rate remains poor and does not exceed 5 % [2]. Most patients are diagnosed with locally advanced or metastatic disease, and their only treatment approach is palliative chemotherapy [3]. Since 1997, single-agent gemcitabine has been regarded as first-line standard of care in metastatic disease. However, subsequently, most gemcitabine-based chemotherapy regimens have not been able to improve OS significantly when compared with alone [4–10]. Only recently, the four-drug regimen FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil and leucovorin) has been shown to improve the objective response rate (ORR), progression-free survival (PFS) and OS compared with single agent gemcitabine, albeit with a significant toxicity profile [11]. In preclinical studies, albumin-bound paclitaxel particles (Nab-P) have been shown to exert antitumor activity as a single agent and synergistic activity in combination with gemcitabine in murine models of pancreatic cancer [12, 13]. On the basis of preclinical evidence, a phase I–II clinical trial of Nab-P combined with gemcitabine showed promising results in previously untreated patients with metastatic pancreatic adenocarcinoma, with a median survival of 12.2 months and manageable safety profile [14]. In a subsequent randomized phase III trial involving 861 patients, this combination was demonstrated to improve OS, PFS and ORR significantly over gemcitabine alone, thus establishing the combination of Nab-P and gemcitabine as standard first-line treatment for metastatic pancreatic cancer [15]. However, based on enrollment criteria, the population of the above trial might have not fully mirrored real-life clinical practice. Therefore, we carried out a retrospective analysis to evaluate efficacy and safety profile of this drug combination in a cohort of 41 patients treated outside clinical trials. Methods Patient population

From January 2012 to May 2014, patients with metastatic pancreatic ductal adenocarcinoma (PDAC), receiving firstline treatment with combination of Nab-P and gemcitabine, were considered eligible for our retrospective analysis.

Written informed consent was obtained from each patient before starting treatment in accordance with the Declaration of Helsinky. The ethics committee of Second University of Naples approved the use of Nab-P plus gemcitabine for compassionate use, on the evidence of good results obtaining in phase I/II trial [14] and the use of date for our retrospective analysis. Inclusion criteria were clinicopathologically confirmed PDAC, age ≥18 years, Karnofsky performance status (KPS) ≥60 %, adequate hematological function (neutrophil count ≥1500/mm3, platelet count ≥100,000/mm3, and hemoglobin ≥ 9 g/dl), adequate hepatic function [total bilirubin 70

11 (26,8 %)

SEX M

18 (43,9 %)

F

23 (56,1 %)

PS (Karnofsky) 100 %

18 (43,9 %)

80–90 %

14 (34.1 %)

60–70 %

9 (21,9 %)

PANCREATIC PRIMARY LOCATION HEAD

24 (58.5 %)

BODY/TAIL

17 (41.5 %)

SITE OF METASTASIS Lung

10 (24,3 %)

Node

7 (17 %)

Liver

30 (73,1 %)

Peritoneum

5 (12,2 %)

Bone

1 (2,4 %)

No OF METASTATIC SITES 1

30 (73,1 %)

≥2

11 (26,9 %)

BILIARY STENT

9 (21.9 %)

MEDIAN CA19.9

469 U/I (17.4–61546)

PREVIOUS SURGERY

11 (26.8 %)

PREVIOUS ADJUVANT GEMCITABINE

10 (24.3 %)

association with sustained DCR (disease control rate) for at least 6 months. Efficacy was evaluated in terms of OS and PFS. The former was defined as the interval between the start of Nab-P and gemcitabine first-line therapy to death or last follow-up visit. The latter was defined as the interval between the start of Nab-P and gemcitabine therapy to clinical progression or death or last follow-up visit if disease did not progress. Safety was monitored by investigators and reported in clinical charts according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0. Variables assessed for prognostic correlations included age ≥70 years, sex, KPS, primary tumor site, baseline CA19-9 level ≥59 × ULN, presence of liver metastases, multiple metastatic involvement, 12-week decrease of CA19-9 level ≥50 % from baseline, basal bilirubin level, neutrophil to lymphocyte ratio (NLR), calculated as the absolute neutrophil count divided by the absolute lymphocyte count measured in × 103/ml, and biliary stent implantation.

Results From January 2012 to May 2014, we retrospectively reviewed the clinical records of 41 patients with PDAC. Activity

The patients received a median of six cycles (range 1– 14) of treatment. Two CRs and 13 PRs were observed for an ORR of 36.6 %. Stable disease was recorded in 14 patients, yielding a global DCR of 70.7 %. Twenty-seven patients reported cancer-related pain or disease-related symptoms before starting treatment; 24 (58.5 %) of them benefitted by at least one point of pain relief according to Numeric Rating Scale or symptom improvement, resulting in a 6-month CBR of 51.2 %. A 12-week decrease of CA19-9 levels ≥50 % from baseline was recorded in 17 patients (41.5 %) (Table 2). Pearson correlation analysis confirmed a positive, linear, statistically significant correlation between CA19-9 decrease ≥50 % from baseline and tumor response (Pearson correlation 0.581, Sig. two-tailed 0.0001). Efficacy

At the time of data censoring, 27 patients had disease progression or had died; median PFS was 6.7 months (95 % CI 5.966–8.034) (Fig. 1). Multivariate analysis showed NLR ≥5 as an independent, negative, prognostic

Table 2 Overall response rate RESPONSE RATE RC

2 (4.8 %)

RP

13 (31.7 %)

ORR

15 (36.6 %)

SD

14 (34.2 %)

DCR

26 (70.7)

PD

12 (29.3)

CA19.9 > 50 % reduction

17 (41.5 %)

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Fig. 1 Progression free survival

indicator (hazard ratio 3.845; 95 % CI 1.611–9.180; p = 0.002). Conversely, 12-week CA 19–9 decrease ≥50 % from baseline was demonstrated to be an independent, positive, prognostic factor (hazard ratio 0.274; 95 % CI 0.09–0.689; p = 0.006). Median PFS of patients with NLR 50 % turned out to be a positive independent

prognostic factor related to PFS. Specifically, median PFS of patients with a decrease from baseline of 50 % had a median PFS of 9 months. NLR >5 was shown to correlate negatively with PFS. Patients with NLR 5 had a median PFS of 3 months. NLR ≥5 was the only variable showing a significant correlation with OS on univariate analysis. Therefore, in accordance with the results of the MPACT trial, our study confirmed both serum levels of CA 19–9 and NLR as outcome predictors in patients with metastatic pancreatic cancer. In particular, NLR prognostic value points to the relevance of systemic inflammatory response in affecting outcome in patients with advanced pancreatic cancer [27, 28].

Table 3 Multivariate analysis PFS

Table 4 Univariate analysis OS UNIVARIATE ANALYSIS (OS) HR

95 % CI

p

AGE

0,78

0,32–1,89

0,6

SEX

0,63

0,28–1,41

0,3

TUMOR SITE

1,2

0,53–2,72

0,6

LIVER METASTASIS

1,61

0,67–3,8

0,3

MULTIPLE METASTASIS

0,9

0,35–2,3

0,8

KPS

1,9

0,58–6,2

0,3

HR

95 % CI

p

BILIARY STENT

1,13

0,44–2,9

0,8

KPS

2,18

0,8–5,9

0,125

BILIRUBIN

1,8

0,8–4

0,1

CA19.9 RESPONSE

0,27

0,1–0,68

0,006

CA19.9 BASELINE

1,75

0,62–4,9

0,3

NLR ≥ 5

3,84

1,6–9,2

0,002

CA19.9 DECREASE

0,59

0,25–1,37

0,2

BILIRUBIN

1,4

0,59–3,3

0,444

NLR ≥ 5

4,3

1,7–10,8

0,002

MULTIVARIATE ANALYSIS (PFS)

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Table 5 Toxicity

2.

AE nab-P + Gem Grade 3 hematologic AE

no (%)

Anemia

3 (7.3 %)

Neutropenia

10 (24.3 %)

Trombocytopenia

5 (12.1 %)

Grade 3 non hematologic AE

no (%)

Fatigue

6 (14.6 %)

Peripheral Neuropathy

5 (12.2 %)

Diarrhea

4 (9.7 %)

Nausea

2 (4.9 %)

3. 4.

5.

6.

7.

Conclusions After years in which the therapeutic options for metastatic pancreatic cancer have been scarce, FOLFIRINOX and Nab-P plus gemcitabine now represent two new options for treatment of metastatic pancreatic adenocarcinoma. In particular, our results confirm the activity, efficacy and tolerability of gemcitabine plus Nab-P as standard first-line treatment in patients with metastatic pancreatic cancer.

8.

9.

10. Acknowledgements The authors certify that no funding was received to conduct this study and/ or for preparation of this manuscript. Availability of data and materials The dataset supporting the conclusions of this article is available on request from e-mail: [email protected].

11.

12. Authors’ contributions FDV participated in the design and coordination of study and drafted the manuscript. JV drafted the manuscript and performed the statistical analysis. AF, MML, TT, AP, AD, AF, BS, GC, ±GG, FC partecipated in coordination of study. °GG performed the statistical analysis. MO participated in coordination of study and helped to draft the manuscript. All authors read and approved the final manuscript.

14.

Competing interests The authors declare that they have no competing interests.

15.

Ethics approval and consent to participate Written informed consent was obtained from the patients for the use of the drug and data according to Declaration of Helsinky. Ethics committee of Second University of Naples approved both the compassionate use of Nab-P plus gemcitabine for and our retrospective analysis on the efficacy of this combination in our clinical practice.

13.

16.

17. 18.

Author details 1 Division of Medical Oncology, Department of Internal and Experimental Medicine “F. Magrassi”, Second University of Naples - School of Medicine, c/o II Policlinico, Via Pansini, 5, 80131 Naples, Italy. 2Division of Medical Oncology, Fatebenefratelli Hospital, Viale Principe di Napoli 14/a, 82100 Benevento, Italy. 3 Divisions of Surgical Oncology, Department of Anesthesiological, Surgical and Emergency Sciences, Second University of Naples - School of Medicine, c/o II Policlinico, Via Pansini, 5, 80131 Naples, Italy.

19.

20.

21. Received: 4 March 2015 Accepted: 4 July 2016 22. References 1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015; 65(1):5–29.

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NAB-paclitaxel and gemcitabine in metastatic pancreatic ductal adenocarcinoma (PDAC): from clinical trials to clinical practice.

Pancreatic adenocarcinoma is an aggressive disease with poor prognosis. In a randomized phase III trial, combination of Nab-paclitaxel (Nab-P) plus ge...
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